Isocyano substituted polystyrene carbonate resin for use in 3 and 4 component condensation reactions

ABSTRACT

This invention relates to compounds comprising isocyano derivatives tethered to solid supports for use in 3 and 4 component condensation reactions. The invention also relates to methods for synthesizing cyclic derivatives by a 3 and 4 component condensation reaction using the compounds of the invention.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to compounds for use in 3 and 4 componentcondensation reactions. The invention also relates to methods forsynthesizing cyclic derivatives by the 3 and 4 component condensationreaction.

[0003] 2. Description of the Related Art

[0004] The multi-component reaction (MCR) is a useful process forpreparing large arrays of diverse compounds. In a typicalmulti-component reaction, three or more starting materials are reactedwith one another simultaneously or almost simultaneously in a one-potreaction. The process does not require the work up of intermediates.

[0005] Multi-component reactions in which one of the components is anisocyanide include the Passerini 3-component reaction (P-3CR); the Ugi4-component reaction (U-4CR) [I. Ugi, Angew. Chem. 1962, 74, 9]; and theUgi 4-component reaction with β-amino acids (U-4CR/β-AS) [I. Ugi et al.,Tetrahedron 1995, 51, 139].

[0006] The Ugi/De-BOC/Cyclization (UDC) strategy has been employed incombination with isocyano compounds in a solution phase synthesis ofconstrained Ugi derivatives (Hulme et al., Tetrahedron Lett. 1998, 39,1113). Conversion of Ugi products derived from (β-isocyano-ethyl)-alkylcarbonates to N-acylated α-amino acids and esters has been reported (Ugiet al., Tetrahedron, 1999, 55, 7411). The solution techniques are notresin bound and are therefore not useful for high speed synthesisbecause of purity problems. The solution/solid phase generation ofγ-lactam analogs has also been reported. This procedure tethers N-BOCaldehydes of an Ugi multi-component reaction to a solid support. BOCremoval and treatment with base affords γ-lactams. (Hulme et al.,Tetrahedron Lett. 2000, 41, 1883). This method suffers in that itresults in the formation of primary amide by-products.

[0007] Cyclic derivatives, such as diketopiperazine anddiketobenzodiazepine ring systems, are found in a wide variety ofcompounds having diverse medicinal utility. Based upon the usefulness ofthese compounds, it would generally be advantageous to have structuresand methods of rapidly and efficiently synthesizing structurally diversederivatives of these and other cyclic compounds, as well as librariescontaining large numbers of such compounds. The present invention meetsthese and other needs.

SUMMARY OF THE INVENTION

[0008] This invention relates to solid supported compounds that are usedin the 3 and 4 component condensation reaction. The invention alsorelates to methods of preparing cyclic derivatives, such asdiketopiperazines or diketobenzodiazepines, using the supportedcompounds of the invention.

[0009] Typically, the methods of the invention employ a multi-componentreaction for the synthesis of intermediate compounds on solid supports.Cyclization of the intermediate compounds results in formation of thedesired cyclic derivative, as well as release of the compound from thesolid support.

[0010] In one embodiment, the invention provides compounds for use in a3 and 4 component condensation reaction, having the formula I:

[0011] wherein X is a solid support, Y and Z are independently alkyl,aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, alkoxyl, aryloxyl,mercapto, alkylthio, arylthio, amino or amido.

[0012] In another embodiment, the invention is a method of synthesizinga cyclic derivative by the 3 or 4 component condensation reaction,comprising combining an aldehyde or ketone, an amine, and anaminocarboxylic acid with a compound of formula I under conditionswhereby a support bound derivative is formed, and cyclizing the supportbound derivative to form the cyclic derivative, followed by release ofthe cyclic derivative from the support.

[0013] In yet another embodiment, the invention is a method ofsynthesizing a cyclic derivative, such as a diketopiperazine compound ora diketobenzodiazepine compound, comprising the steps of forming anisocyano derivative on a solid support; combining an aldehyde or ketone,an amine, and an aminocarboxylic acid with the isocyano derivative underconditions whereby a bisamide is formed on the solid support; andcyclizing the support bound bisamide to form a cyclic derivative,followed by release of the cyclic derivative from the support.

[0014] In still another embodiment, the invention is directed tocompounds of formula II(a), II(b) and II(c);

[0015] wherein X, Y and Z are as defined for formula I.

[0016] In a further embodiment, the invention is directed to a method ofpreparing a compound of formula II, as depicted in Example 1, below.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The convertible isonitrile resins described herein offer resinbound isonitrile functionalities that can be used in 3 and 4 componentcondensations without any primary amide by-product formation as seenwith the immobilized cyclohexenyl isonitrile resin. The isonitirileresins of the invention are much less expensive to manufacture than thesafety catch linker isonitrile resin. These resins can be made inessentially two steps, so they are also much easier to manufacture thaneither the immobilized cyclohexenyl isonitrile resin or the safetycatch-linker isonitrile resin. This invention also provides methods ofusing isonitrile resins to synthesize cyclic derivatives.

[0018] Definitions

[0019] The following definitions are set forth to illustrate and definethe meaning and scope of the various terms used to describe theinvention herein.

[0020] “Acyl” denotes groups —C(O)R, where R is alkyl or substitutedalkyl, aryl, or substituted aryl as defined below.

[0021] “Alkyl” or “lower alky” refer interchangeably to a cyclic,branched or straight chain, alkyl group of one to eight carbon atoms.This term is further exemplified by such groups as methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl),cyclopropylmethyl, i-amyl, n-amyl, and hexyl. Preferred groups aremethyl, sec-butyl, iso-butyl and iso-propyl. “Substituted lower alkyl”refers to lower alkyl as just described including one or more functionalgroups such as lower alkyl, aryl, aralkyl, acyl, halogen, hydroxyl,amino, mercapto and the like. These groups may be attached to any carbonatom of the lower alkyl moiety. Preferred groups are 2-guanidinopropyl,2-carboxymethyl, 2-amidomethyl, thiomethyl, 2-carboxyethyl,2-amidoethyl, 3-imidazolylmethyl, 4-aminobutyl, 3-hydroxyl-4-aminobutyl,2-(methylthio)ethyl, hydroxymethyl and 1-hydroxyethyl.

[0022] “Alkenyl” generally refers to a lower alkyl substituent havingone or more double bonds, such as ethenyl and substituted forms thereof.“Alkynyl” refers herein to a lower alkyl substituent having one or moretriple bonds, such as ethynyl. “Substituted alkenyl” and “substitutedalkynyl” refer to an alkenyl or an alkynyl as just described includingone or more functional groups such as lower alkyl, aryl, aralkyl, acyl,halogen, hydroxyl, amino, acylamino, acyloxy, alkoxyl, mercapto and thelike.

[0023] “Alkoxyl” denotes the group —OR, where R is lower alkyl,substituted lower alkyl, aryl, substituted aryl, aralkyl or substitutedaralkyl as defined below.

[0024] “Alkylthio” denotes the group —SR, where R is lower alkyl,substituted lower alkyl, aryl, substituted aryl aralkyl or substitutedaralkyl as defined below.

[0025] “Amido” denotes the group —C(O)NRR′, where R and R′ mayindependently be hydrogen, lower alkyl, substituted lower alkyl, aryl,substituted aryl as defined below or acyl.

[0026] “Amino” denotes the group NRR′, where R and R′ may independentlybe hydrogen, lower alkyl, substituted lower alkyl, aryl, substitutedaryl as defined below or acyl.

[0027] “Amino Acid Derivative” as used herein, refers generally to bothnatural and unnatural amino acids, preferably an α- or β-amino acid,which may or may not be modified by the addition of one or moreprotecting groups, such as 9-fluorenylmethyloxycarbonyl (Fmoc), benzylor t-butoxycarbonyl (BOC), and/or activating groups or by its couplingto a solid support.

[0028] “Aralkyl” refers to the group -R-Ar where Ar is an aryl group andR is straight-chain or branched-chain aliphatic group. Aralkyl groupscan optionally be unsubstituted or substituted with, e.g., halogen,lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, loweracyloxy, and hydroxy. Preferred aralkyl groups include benzyl,hydroxybenzyl, methylbenzyl, chlorobenzyl, bromobenzyl, iodobenzyl,thiobenzyl, aminobenzyl, napthylmethyl and hydroxynapthylmethyl.

[0029] “Aryl” or “Ar” refers to an aromatic carbocyclic group having atleast one aromatic ring (e.g., phenyl or biphenyl) or multiple condensedrings in which at least one ring is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).Preferred substituents are phenyl and napthyl. “Substituted aryl” refersto aryl optionally substituted with one or more functional groups, e.g.,halogen, lower alkyl, lower alkoxyl, lower alkylthio, trifluoromethyl,lower acyloxyl, hydroxyl and the like. Preferred groups includemethylphenyl, chlorophenyl, iodophenyl, bromophenyl, 4-hydroxyphenyl,thiophenyl, 4-chlorothiophenyl, 2-methylthiophenyl and4-methylsulfonylphenyl.

[0030] “Aryloxyl” denotes groups -OAr, where Ar is an aryl orsubstituted aryl group as defined below.

[0031] “Halogen” refers to fluorine, bromine, chlorine, and/or iodineatoms.

[0032] “Heteroaryl” or “HetAr” refers to an aromatic carbocyclic grouphaving a single ring (e.g., pyridyl or furyl) or multiple condensedrings (e.g., naphthyridinyl, quinoxalyl, quinolinyl, indolizinyl orbenzo[b]thienyl) and having at least one hetero atom, such as N, O or S,within the ring. “Substituted heteroaryl refers to heteroarylsubstituted with, e.g., halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, lower acyloxy, and hydroxy. Preferredheteroaryl groups include indolyl, methylindolyl, imidazolyl,N-methylimidazolyl and methylimidazolyl.

[0033] “Heteroarylalkyl” refers to the group -R-HetAr where HetAr is anheteroaryl group and R is straight-chain or branched-chain aliphaticgroup. Heteroarylalkyl groups can optionally be unsubstituted orsubstituted with, e.g., halogen, lower alkyl, lower alkoxyl, loweralkylthio, trifluoromethyl, lower acyloxy, and hydroxy. Preferredheteroaralkyl groups include 3-indolylmethyl and 2-imidazolylmethyl.

[0034] “Hydroxyl” refers to the group —OH.

[0035] A preferred compound of the invention is of the formula II

[0036] As depicted herein, X represents the un-illustrated portion ofthe solid support.

[0037] The Solid Support

[0038] Solid supports upon which the cyclic derivatives can besynthesized may include glass, latex, silica gel, cross-linkedpolystyrene and other similar polymers and resins, gold and othercolloidal metal particles.

[0039] Preferred supports include Hydroxymethyl Polystyrene Resin(100-200 mesh) (substitution: 1.29 meq/g from Colorado BiotechnologyAssociates, Inc.).

[0040] Preferably, the solid support contains pendent alcohol groupswhich can be converted to a chloroformate for further reaction (seee.g., example 1, below). Alternatively, although less preferably, thealcohol can be converted to a p-nitrophenyl carbonate for furtherreaction.

[0041] The Isocyano Functionality

[0042] Introduction of an isocyano functional group onto the polymersupport is done by reacting an isocyano containing compound with thesupport under conditions that provide coupling.

[0043] The isocyano containing compound should contain an isocyanofunctional group and at least one other functional group capable ofcoupling with the solid support. Example 2 depicts one example of anisocyano containing compound and Example 1 depicts coupling of thiscompound with the functionalized solid support. In these examples, thecoupling functional groups on the support and the isocyano containingcompound are, respectively, chloroformate and alkoxide.

[0044] The following examples are illustrative of the invention, but donot serve to limits its scope.

EXAMPLES Example 1

[0045] The synthesis of (β-isocyanoethyl)-polystyrene carbonate resin isshown in Scheme 1.

[0046] 205 g of Hydroxymethyl Polystyrene Resin (100-200 mesh)(substitution: 1.29 meq/g from Colorado Biotechnology Associates, Inc.)is washed with 4 L of toluene and 2 L of pentane and then placed underhigh vacuum overnight for drying. The dry resin is then placed in a 3necked 5 L round bottom flask fitted with an automatic overhead stirpaddle. The resin is then swollen with 3 L of toluene (DriSolve). Next,a 20% phosgene in toluene solution (3 equiv., 410 mL) is added via anaddition funnel with a steady flow rate of addition. Upon completeaddition, the reaction is stirred for 30 minutes at room temperature.The resin is then filtered using a 3 L fritted (C) funnel and washedwith 2 L of toluene (DriSolve). The resin is returned to the 3 necked 5L round bottom flask and the reaction is repeated a second time. Uponfiltration the second time, the resin is washed with 1 L of toluene and1 L of THF. The resin is then returned to the 3 necked round bottomflask and diluted with 3 L of THF. The resin is then cooled to 0° C inan ice/H₂O bath over 1 h. The lithium alcoholate (prepared in Scheme 2)is then cannulated in at a steady flow rate. Upon complete addition ofthe alcoholate, the reaction is stirred for 5 min and then filtered. Theresin is washed with THF (1 L), MeOH (2 L), DCM (1 L), and pentane (1L). The resin is then dried overnight under high vacuum. 234 g of resinwere recovered and shown to have a loading of 0.87 mmol/g bymicroanalysis (Schwarzkopf Microanalytical Laobratory, Inc.). A traceamount of chlorine is found to be also present. IR 2150 cm⁻¹.

[0047] To a 1 L flame dried round bottom flask are added 270 mL DriSolveTHF and 26 g of 4,4-dimethyl-2-oxazoline (1 equivalent with respect toHydroxymethyl Polystyrene Resin). The solution is cooled to −78° C. anda 2.5 M solution of BuLi in hexanes (127 mL, 1.2 equiv.) is added viasyringe while vigorously stirring. The color dissipates at first but thesolution stays dark orange upon complete addition. The reaction isstirred for 1 h at −78° C. under N₂ before cannulation into the resinbound chloroformate (see Scheme 1).

Example 2

[0048] A multi-component reaction utilizing the(β-isocyanoethyl)-polystyrene carbonate resin prepared in example 1 isillustrated in Scheme 3.

[0049] A 1.2 M solution of 2-chlorobenzylamine (1.1 mmol, 133 μL) and2-phenylpropionaldehyde (1.1 mmol, 146 μL) in trimethyloithoformate(tmof) is made and allowed to react for 30 minutes. 126 mg (110 μmol) of(β-isocyanoethyl)alkylcarbonate resin (substitution:0.87 meq/g (seeScheme 1)) is swollen for 15 minutes in 1.75 mL of DCE in a 5 mL Bohdanfritted reaction tube. The 1.2 M solution of imine in tmof is then addedto the resin followed by a 1.2 M solution of Boc-DL-alanine intrifluoroethanol (tfe). The reaction is then shaken at room temperaturefor 3 days. The reaction is then filtered and washed with DCE (3×2 mL),MeOH (3×2 mL), and pentane (2 mL). Absence of isonitrile stretch in theIR.

Example 3

[0050] Cyclization and release of the cyclic derivative from the supportare illustrated in Scheme 4.

[0051] The resin bound 4 component condensation product (see Scheme 3)is swollen in THF (1.8 mL). 1 M KO'Bu in THF (2 equiv, 220 μL) is addedand the reaction is shaken at room temparature overnight. NaOMe (1equiv) is then added and the reaction allowed to stir at roomtemperature for an additional 5 h. The reaction is then filtered into atest tube using a vac master and washed with THF (3×1 mL). The solutionis transferred to a 20 mL round bottom flask and concentrated on arotovap at 50° C. The sample is then triturated with DCM (4×500 μL). Thetriturate is then placed in a 10 mL round bottom flask and treated with900 μL of TFA. The reaction is allowed to sit overnight at roomtemperature. The reaction is then concentrated on the rotovap andredissolved in 2 mL of TVF. TMA-Carbonate (Silicycle, 0.73 mmol/g, 2equiv) is added to the reaction and allowed to stir for 2 h. Next,isocyanate-3 (Silicycle, 1.3 mmol/g, 1.5 equiv) is added to the reactionand allowed to stir for an additional 2 h. The reaction is then filteredthrough a fritted Bohdan tube into a test tube and transferred to a 10mL round bottom flask and concentrated to give the diketopiperazineproduct. MS pos APCI hfba/acn infusion showed m/z=357.

Example 4

[0052] Preparation of a benzodiazepine product by a multi-componentreaction is illustrated in Scheme 5.

[0053] The same procedure as followed for Schemes 3 and 4 is followedhere, except 2-methylbutyraldehyde (1.1 mmol, 118 μL) is used instead of2-phenylpropionaldehyde, the hydrochloric salt of N-methylanthranilicacid (1.1 mmol, 206 mg) is used instead of BOC-DL-alanine, andcyclopentylamine (1.1 mmol, 108 μL) is used instead of2-chlorobenzylamine, in the four component condensation reaction usingthe isonitrile resin shown in Scheme 1. This gave thebenzodiazepinedione product. MS pos esi m/z=315.

What is claimed is:
 1. A compound of the formula:

wherein X is a solid support, Y and Z are independently alkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, acyl, alkoxyl, aryloxyl, mercapto,alkylthio, arylthio, amino or amido.
 2. The compound of claim 1 whereinY is alkyl.
 3. The compound of claim 1 wherein Z is alkyl.
 4. Thecompound of claim 1 wherein Y is methylene and Z is isobutylene.
 5. Acompound according to claim 1 comprising:

wherein X is as solid support.
 6. A compound according to claim 1comprising (β-isocyanoethyl)-polystyrene carbonate resin.
 7. A method ofsynthesizing a cyclic derivative by a 3 or 4 component condensationreaction, comprising: combining an aldehyde or ketone, an amine, and anaminocarboxylic acid with the compound of claim 1 under conditionswhereby a support bound derivative is formed; cyclizing the supportbound derivative to form a cyclic derivative.
 8. The method of claim 7wherein the cyclizing of the support bound derivative is carried out inpotassium t-butoxide/sodium methoxide/trifluoroacetic acid.
 9. Themethod of claim 7 wherein said cyclizing of the support bound derivativeto form a cyclic derivative releases the cyclic derivative from thesolid support.
 10. The method of claim 7 wherein the support boundderivative is a bisamide.
 11. The method of claim 7 wherein the cyclicderivative is a diketopiperazine derivative
 12. The method of claim 7wherein the cyclic derivative is a benzodiazepinedione derivative.
 13. Amethod of synthesizing a diketopiperazine derivative or adiketobenzodiazepine derivative, comprising the steps of: forming anisocyano derivative on a solid support; combining an aldehyde or ketone,an amine, and an aminocarboxylic acid with the isocyano derivative underconditions whereby a bisamide is formed on the solid support; cyclizingthe support bound bisamide to form a diketopiperazine derivative or adiketobenzodiazepine derivative.
 14. The method of claim 13 wherein thesolid support is hydroxymethyl polystyrene resin.
 15. The method ofclaim 13 wherein the isocyano derivative is lithium2-isocyano-2-methylpropoxide.
 16. The method of claim 15 wherein saidforming of the isocyano derivative on the solid support is carried outby the steps comprising: (a) converting the solid support to achloroformate derivative; and (b) combining the lithium2-isocyano-2-methylpropoxide with the solid support of step (a).
 17. Themethod of claim 13 wherein the aldehyde or ketone is2-phenylpropionaldehyde, the amine is 2-chlorobenzylamine and theaminocarboxylic acid is Boc-DL-alanine.
 18. The method of claim 13wherein the aldehyde or ketone is 2-methylbutyrlaldehyde, the amine iscyclopentylamine and the aminocarboxylic acid is the hydrochloric saltof N-methylanthranilic acid.
 19. The method of claim 13 wherein thecyclizing of the support bound bisamide to form a diketopiperazinederivative releases the diketopiperazine derivative from the solidsupport.
 20. The method of claim 13 wherein the cyclizing step iscarried out in potassium t-butoxide/sodium methoxide/trifluoroaceticacid.
 21. The method of claim 13 wherein said combining of the isocyanoderivative with the solid support forms a compound of the structure:

wherein X is a solid support, Y and Z are independently cyclic, branchedor straight chain C₁-C₈ alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,acyl, alkoxyl, aryloxyl, mercapto, alkylthio, arylthio, amino or amido.